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Aminobenzimidazoles and Structural Isomers as Templates for Dual‐Acting Butyrylcholinesterase Inhibitors and h CB 2 R Ligands To Combat Neurodegenerative Disorders
Author(s) -
Dolles Dominik,
Nimczick Martin,
Scheiner Matthias,
Ramler Jacqueline,
Stadtmüller Patricia,
Sawatzky Edgar,
Drakopoulos Antonios,
Sotriffer Christoph,
Wittmann HansJoachim,
Strasser Andrea,
Decker Michael
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500418
Subject(s) - pharmacophore , butyrylcholinesterase , chemistry , agonist , docking (animal) , stereochemistry , affinities , combinatorial chemistry , receptor , biochemistry , acetylcholinesterase , aché , enzyme , medicine , nursing
A pharmacophore model for butyrylcholinesterase (BChE) inhibitors was applied to a human cannabinoid subtype 2 receptor ( h CB 2 R) agonist and verified it as a first‐generation lead for respective dual‐acting compounds. The design, synthesis, and pharmacological evaluation of various derivatives led to the identification of aminobenzimidazoles as second‐generation leads with micro‐ or sub‐micromolar activities at both targets and excellent selectivity over h CB 1 and AChE, respectively. Computational studies of the first‐ and second‐generation lead structures by applying molecular dynamics (MD) on the active h CB 2 R model, along with docking and MD on h BChE, has enabled an explanation of their binding profiles at the protein levels and opened the way for further optimization. Dual‐acting compounds with “balanced” affinities and excellent selectivities could be obtained that represent leads for treatment of both cognitive and pathophysiological impairment occurring in neurodegenerative disorders.